The term "prolactin agonist" as used herein means any compound that has prolactin-like activity, or which increases the number of lactogenic (prolactin-recognizing) receptors on cells. This includes, but is not limited to, prolactin, peptide sequences from prolactin that have prolactin-like activity, growth hormone, peptide sequences from growth hormone which have prolactin-like activity, placental lactogens, and any genetically engineered protein sequence which has prolactin-like activity, or which up-regulates or stimulates lactogen receptors when administered to the intact animal.
The immune system is a highly complex system of cells and tissues that require the cooperation and interaction of a large number of different cell types. The systems of the body comprising the immune system network have been characterized as belonging to the hematopoietic system, the reticuloendothelial or phagocytic system and the lymphoid system.
The hematopoietic system is located in the bone marrow and is responsible for supplying the various precursor and accessory cells of the immune system. The reticuloendothelial system is comprised of the phagocytic cells responsible for destroying or neutralizing foreign substances that may have entered the body. The lymphoid system is comprised of lymphocytes and is responsible for the overall regulation of the immune system and the production of antibodies. Certain cells of the immune system also can secrete factors which greatly augment phagocytic cell function.
The main tissues of the lymphoid system involved in the immune response include the bone marrow and the thymus. Marrow fills the central core of nearly all bones in mammals. The bone marrow contains hematopoietic tissue which is responsible for the formation of erythrocytes, platelets, granulocytes and monocytes and lymphocyte precursors. The thymus is a pouch of epithelial cells filled with lymphocytes, nourished and drained by the vascular and lymphatic systems and innervated by the autonomic nerves. The human thymus is a fully developed organ at birth and weighs 15 to 20 grams. By puberty, it weighs approximately 40 grams, after which it atrophies or involutes as age progresses.
Lymphocytes can be generally classified as either T-lymphocytes or B-lymphocytes. While all lymphocytes are derived from stem cells in the bone marrow, these lymphocyte precursors circulate in the blood through the various organs. Lymphocytes that pass through the thymus become differentiated into either T or B lymphocytes and acquire special functions associated with this differentiation. Most B-lymphocytes have a short life span of approximately 5-7 days and are responsible for the production of antibodies in response to challenge by a particular antigen. T-lymphocytes are smaller than B-lymphocytes and have a life span measured in months or even years. T-lymphocytes are responsible for the general regulation of the immune system and are the principal mediators in cell-mediated immune responses.
B-lymphocytes respond to immunologic phenomena very differently from T-lymphocytes in practically every instance. B-lymphocytes synthesize specialized antibodies in response to the presence of a specific antigen. Specific subtypes of "T"-lymphocytes can augment or suppress this function. Subsequent introduction of the same antigen causes a rapid production of large amounts of the specific antibody causing a rapid elimination of the disease-causing substance.
When T-lymphocytes contact a recognizable antigen in the appropriate context, they pass through a phase of growth and cell division known as lymphocyte transformation or proliferation. This transformation causes the specific, antigen-recognizing T-lymphocytes to produce a large population of their own kind. The antigen is recognizable to a T-lymphocyte only after it has been "processed" by macrophages and properly presented to the T-lymphocyte.
The term "cell-mediated immunity" is used to refer to killing of tumor cells or pathogenic microorganisms either directly by activated "T"-lymphocytes, or by augmented phagocytic cell function resulting from proliferation and secretion of soluble "activation factors" by T-lymphocytes recognizing a specific antigen. This is in contrast to "humoral immunity" which refers to the protective effects of specific antibody secreted by "B"-lymphocytes.
Suppression of the immune system is a clinical disorder found in patients having a variety of illnesses. For example, an increase in the incidence of infectious disease has been reported in chronic narcotic users, such as opioid addicts. These addicts appear to have a reduction of T-lymphocyte number and function. In animal models, treatment with opioids has been shown to inhibit lymphocyte proliferative responses, natural killer cell activity, antibody production and circulating levels of interferon. (See Bryant, Henry U. et al., Immunosuppressive Effects of Chronic Morphine Treatment in Mice, Life Sciences, 41:17311 738, 1987).
Cancer patients often exhibit a suppressed immune response. This immunosuppression is most likely caused by agents used to treat the cancer as well as by factors secreted by the cancer cells themselves. Most anti-cancer agents, such a radiation therapy and chemotherapy, inadvertently destroy lymphocytes and other cells important to the immune system. Some tumors, such as the tumors in Hodgkin's disease, release or induce the release of immunosuppressive factors. Hodgkin's disease patients exhibit an abnormally high sensitivity to intracellular parasitic infections such as tuberculosis and herpes virus infections.
Critically ill patients, such as those with severe burns or complications of sepsis or of multiple trauma, many of whom have been treated with dopamine infusions, often demonstrate suppressed immune function, particularly of cell-mediated immunity. Dopamine is normally administered to patients suffering from hemodynamic imbalances caused by shock syndrome due to disorders such as myocardial infarctions, trauma, endotoxic septicemia, open heart surgery, renal failure and congestive heart failure.
Chronic severe stress has also been associated with depressed immune function. As an example, lymphocytes isolated from individuals exposed to psychosocial stress, such as bereavement, appear to proliferate subnormally, resulting in an impaired immune response. (See Schleifer, S. J., et al., Suppression of lymphocyte stimulation following bereavement, JAMA, 250:374-377 (1983)) Another case of stress-induced immunosuppression can be found in burn patients. The combination of an ineffectual skin barrier to airborne infections in combination with stress-induced immunosuppression could be the cause of a high mortality rate among these patients.
It is believed the impaired immune response associated with stress is due, in part, to an increased secretion of adrenal corticosteroids from the adrenal glands in response to the stress. However, research has indicated that immunosuppression caused by stress is not solely due to the elevated levels of corticosteroids. A similar suppression of lymphocyte proliferative response in rats following repeated foot shock is evident even after the adrenal glands have been surgically removed.
Patients are often treated with high doses of adrenal corticosteroids or synthetic analogs for several days, or are treated with moderate doses for a longer period of time, to reduce inflammation due to disorders such as inflammatory bowel disease, brain edema secondary to tumor, surgery, or radiation therapy and severe asthma. As described above, the resulting elevated levels of corticosteroids often result in the impairment of immune function as an unwanted side-effect.
The mechanism resulting in immunosuppression by corticosteroid hormones is still poorly understood. Direct toxicity to immune cells and their precursors is not seen at the doses of corticosteroids used clinically. While corticosteroids are known to suppress production of immune cell growth factors such as interleukin-2 when added to cultured lymphocytes, this effect only partially accounts for the suppressive effects they have in the whole animal. We have found that down regulation of prolactin receptors by corticosteroids probably is a major mechanism by which, in the intact animal, they suppress immune function (see below in Detailed Description of Invention and below, Examples 10, 11, and 12). This discovery underlies the efficacy of the present invention in the particular use of preventing glucocorticoid immunosuppression, inasmuch as it has been found the invention can prevent this down-regulation of prolactin receptors.
Patients who receive exogenous adrenal corticosteroids or synthetic analogs for extended periods of time often develop an impaired ability to secrete endogenous steroid hormones, such as cortisol, due to marked atrophy of the adrenal cortex. When these patients are taken off the exogenous hormone therapy, they can suffer from adrenal insufficiency. Such an insufficiency can be detrimental to patients having an infection, recovering from surgery, or suffering from other stresses because these circumstances give rise to an increased demand for adrenal cortical hormones.
What is needed is a composition that will safely and effectively modulate the immune or adrenal systems of an animal or human to prevent the deleterious effects of stress or corticosteroid-treatment on their function, or to stimulate immune, or bone marrow function when it is impaired due to accidental or therapeutic exposure to radiation or to toxins. Such a composition would preferably be a natural substance to reduce the possibility of adverse side effects.